Tamoxifen as an ERalpha antagonist is an effective chemopreventive agent against breast cancer. The soy isoflavones genistein and daidzein are ER (alpha and beta) agonists and antagonists. Theoretically, soy isoflavones may enhance or may negate tamoxifen's chemopreventive effects. Women at high risk for developing breast cancer due to family history, or breast cancer patients with ER+ nodes, are treated with tamoxifen for 5 years to prevent breast cancer or tumor metastasis respectively. It is presently uncertain if these women are benefitted or harmed by consuming soy products, or by taking phytoestrogens as supplements. Our recent preliminary studies in the DMBA-induced mammary carcinogenesis rat model suggest that soy compound(s) enhance tamoxifen's chemopreventive action. However, we do not know if this increased protection is due to the antiestrogenic/antiproliferative effects of tamoxifen combined with those of soy phytoestrogens (genistein and daidzein) are mediated through ERalpha. It is possible that soy phytoestrogens may inhibit tumor cell proliferation by binding to the ERbeta. Alternatively, phytoestrogens or other soy ingredients may combine their antioxidant effects with those of tamoxifen to provide enhanced protection against tumor initiation or promotion. We hypothesize that soy-containing diets will enhance tamoxifen's cancer chemopreventive effects in the DMBA/mammary carcinogenesis rat model. The predicted mechanism of action is that tamoxifen acts as an antagonist with ERalpha (in the mammary gland) and genistein acts as an agonist with ERbeta. We will determine if the combined effect of tamoxifen and soy is due to the estrogenic/antiestrogenic effects of the agents, or due to their antioxidant effects. The specific aims designed to directly test our hypothesis are: (1) Evaluate the combined effects of tamoxifen with diets containing semi-crude extracts of soy or with purified soy phytoestrogens (genistein and daidzein) against DMBA induced mammary carcinogenesis in female rats. (2) Identify the mechanism of the anticipated additive/synergistic chemopreventive effect between tamoxifen and the active soy component.